OVERALL RESEARCH PLAN - ABSTRACT / SUMMARY In the U.S., low dose aspirin (LDA) is one of the most widely used medications given its established role in the secondary prevention of cardiovascular disease (CVD). In recent years, several expert bodies, including the U.S. Preventive Services Task Force (USPSTF), have recommended the routine use of LDA for the primary prevention of both CVD and colorectal cancer (CRC) based on substantial data from prior randomized controlled trials (RCTs) primarily conducted among younger adults. However, for adults aged 70+, the USPSTF deemed current evidence supporting a net benefit insufficient. Furthermore, the need to prolong healthy independent life, free of dementia and significant disability, is critical given the rising social and economic costs of the increasingly aging population. To address these knowledge gaps, the NIA/NCI- sponsored ASPirin in Reducing Events in the Elderly (ASPREE) study was developed as a ground-breaking RCT that recruited 19,114 initially healthy older individuals aged 70+ years (65+ for U.S. minorities) from 2010- 2014 in the U.S. and Australia to examine whether initiation of 5 years of low-dose daily aspirin (LDA; 100 mg/day) prolonged the healthy lifespan of older adults. In June 2017, the randomized treatment phase of ASPREE was suspended after a median of 4.6 years of treatment due to lack of an effect of LDA on the primary outcome of disability-free survival (DFS). For secondary outcomes, LDA unexpectedly was associated with an increased risk of all-cause mortality (HR 1.14; 95% CI, 1.01,1.28) driven by an excess of deaths due to cancer, despite no increase in incident cancer. Furthermore, LDA showed a trend toward lower incident physical disability overall. These provocative initial findings obligate continued study and follow-up of the ASPREE cohort through this U19 proposal. Our overall goal is to generate fundamental knowledge about the role of aspirin in older adults, a population in which aspirin's risk/benefit for primary prevention of chronic disease has been understudied. Our overarching hypothesis is that extended follow-up of the ASPREE cohort will demonstrate a long-term `legacy' benefit of LDA on cancer, dementia and disability. We further hypothesize that extensive genomic, biochemical, and imaging correlates collected during follow-up will offer unique biological insight into LDA's effects on these endpoints that may lead to mechanistically-inspired biomarkers for more `precision' prevention approaches to chronic disease prevention. Thus, we propose to establish ASPREE-XT to extend follow-up in ASPREE participants over the next 5 years to pursue three Projects focused on cancer, dementia (including Alzheimer's), and physical disability that will be supported by 6 Cores, facilitating synergy and collaboration. Together, this U19, led by a multidisciplinary, international team of leading investigators, will provide an unprecedented opportunity to define the long-term efficacy of LDA to guide clinical recommendations and offer fundamental insights into the biological underpinnings of the leading causes of dementia, disability and death among older adults.